The long-term goal is to determine the mechanism of the profound changes in affective state and cognitive functions that are produced by hallucinogenic drugs. This competing renewal application moves beyond research in cells and isolated tissues - the primary focus of the first five years of this grant - to new research strategies involving the intact brain and whole animal. The experimental design combines molecular, pharmacological and behavioral approaches to achieve four specific aims. First, the pattern of activation of 5-HT2A and 5-HT2C receptors will be mapped in brains of rats treated with lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), and (-)- 1 -(4-bromo-2,5-dimethoxyphenyl)-2- aminopropane (DOB). Hallucinogen-induced expression of c-fos mRNA, determined by solution and in situ hybridization in brains of rats, will serve as an index of serotonin receptor activation. Contributions of 5- HT2A and 5-HT2C receptors to the c-fos signal will be evaluated using selective antagonists or antisense oligodeoxynucleotides to block synthesis of a single receptor subtype. Specific Aim 2 will probe the role of 5-HT2A and 5-HT2C receptors in the discriminative stimulus effects of the three hallucinogenic drugs. Rats will be trained to discriminate LSD, DMT or (-)DOB from saline as a model of the subjective effects of hallucinogenic drugs. Treatments established in specific aim 1 for selective inhibition of each of the receptors will be evaluated. Specific Aim 3 will localize the brain site(s) mediating the discriminative stimulus effects of hallucinogens by intracerebral microinjection of hallucinogens or of selective antagonists directly into specific brain sites. The functional consequences of these localized injections will be investigated using drug-discrimination and c-fos mRNA expression. The final aim will determine if tolerance develops to activation of 5-HT2A and/or 5-HT2C receptors and correspondingly to the subjective behavioral effects of hallucinogens. These various investigations will elucidate the in vivo actions of hallucinogenic drugs at brain 5-HT2A and 5-HT2C receptors and define the importance of these two receptors in the subjective effects of hallucinogens. Such studies may pave the way for clinical investigations into the role of these receptors in the profound brain-altering properties of hallucinogenic drugs.